Consumer medicine information

APO-Latanoprost

Latanoprost

BRAND INFORMATION

Brand name

APO-Latanoprost

Active ingredient

Latanoprost

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Latanoprost.

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

APO-LATANOPROST is used to lower raised pressure in the eye and to treat glaucoma. Glaucoma is a condition in which the pressure of fluid in the eye may be high. However, some people with glaucoma may have normal eye pressure.

Glaucoma is usually caused by a build-up of the fluid which flows through the eye. This build up occurs because the fluid drains out of your eye more slowly than it is being pumped in. Since new fluid continues to enter the eye, joining the fluid already there, the pressure continues to rise. This raised pressure may damage the back of the eye resulting in gradual loss of sight. Damage can progress so slowly that the person is not aware of this gradual loss of sight. Sometimes even normal eye pressure is associated with damage to the back of the eye.

There are usually no symptoms of glaucoma. If glaucoma is not treated it can lead to serious problems, including total blindness. In fact, untreated glaucoma is one of the most common causes of blindness.

How APO-LATANOPROST works

APO-LATANOPROST belongs to a family of medicines called prostaglandin agonists.

It lowers the pressure in the eye by allowing more fluid to flow out from within your eye.

Although APO-LATANOPROST helps control your glaucoma it does not cure it. So, you must keep using it until your doctor tells you to stop.

APO-LATANOPROST is used, either alone or in combination with other eye medicines, to lower raised pressure within your eye.

Ask your doctor if you have any questions about why APO-LATANOPROST has been prescribed for you. Your doctor may have prescribed it for another reason.

APO-LATANOPROST is not addictive.

Use in Children

APO-LATANOPROST is not recommended for use in children.

The safety and effectiveness of APO-LATANOPROST in children have not been established.

Before you use APO-LATANOPROST

When you must not use it

Do not take this medicine if you have an allergy to:

  • any medicine containing latanoprost
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine after the expiry date printed on the pack or if the bottle or packaging shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using APO-LATANOPROST, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions such as severe asthma, or any other types of glaucoma or eye conditions.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and APO-LATANOPROST may interfere with each other. These include:

  • eye drops which contain an ingredient called thiomersal. If using such eye drops as well as APO-LATANOPROST, you should wait at least 5 minutes between using these eye drops and APO-LATANOPROST
  • some other eye drops that contain a prostaglandin. The use of two or more prostaglandin eye drops at the same time is not recommended.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the directions, ask your doctor or pharmacist for help.

If you are being changed from one eye drop to another, follow your doctor's instructions carefully as to when to stop the old drops and when to start the new drops.

How much to use

The usual dose of APO-LATANOPROST is one drop into the affected eye, or eyes, once daily.

Use APO-LATANOPROST every day, at about the same time each day, preferably in the evening, unless your doctor tells you otherwise. Using your eye drops at the same time each day will have the best effect on your eye pressure. It will also help you remember when to use the eye drops.

How to use it

If you are wearing soft contact lenses, remove them before putting the drops in your eye. The preservative in APO-LATANOPROST (benzalkonium chloride) may be deposited in soft contact lenses. You can put your soft contact lenses back into your eyes 15 minutes after you have used APO-LATANOPROST.

If using other eye drops in addition to APO-LATANOPROST, wait at least 5 minutes before putting any other drops in your eye(s).

Be careful not to touch the dropper tip against your eye, eyelid or anything else. Touching the dropper tip against something may contaminate the eye drops and give you an eye infection.

You may find it easier to put drops in your eye while you are sitting or lying down.

  1. Wash your hands well with soap and water.
  2. Twist off the protective overcap from the bottle.
  3. Unscrew the inner cap.
  4. Use your finger to gently pull down the lower eyelid of your affected eye.
  5. Tilt your head back and look up.
  6. Place the tip of the bottle close to but not touching your eye. Squeeze the bottle gently so that only one drop goes into your eye, then release the lower eyelid.
    Close your eye. Do not blink or rub your eye.
  7. While your eye is closed, place your index finger against the inside corner of your eye and press against your nose for about two minutes. This will help to stop the medicine from draining through the tear duct to the nose and throat, from where it can be absorbed into other parts of your body. Ask your doctor for more specific instructions on this technique.
  8. Screw the inner cap back on the bottle.
  9. Wash your hands again with soap and water to remove any residue.

You may feel a slight burning sensation in the eye shortly after using the eye drops.

If this persists, or is very uncomfortable, contact your doctor or pharmacist.

How long to use it

Continue using APO-LATANOPROST every day for as long as your doctor prescribes. APO-LATANOPROST helps control your condition but does not cure it.

If you forget to use it

If you miss a dose, skip the dose you missed and use your next dose when you are meant to. If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not use double the amount to make up for the dose that you missed.

If you use too much (overdose)

If you accidentally put several drops in your eye, immediately rinse your eye with warm water.

If you think that you or anyone else may have swallowed APO-LATANOPROST, immediately telephone your doctor or the Australian Poisons Information Centre (telephone 131 126) for advice or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

While you are using this medicine

Things you must do

To make sure APO-LATANOPROST is working properly, have your eye pressure checked regularly.

Have your eyes checked regularly for any other changes, including a change in eye colour. A slow change in eye colour, which may be permanent, has been reported to occur in some patients who use APO-LATANOPROST. Your doctor will decide whether you should continue using APO-LATANOPROST.

If you develop an eye infection, receive an eye injury, or have eye surgery tell your doctor. Your doctor may tell you to use a new container of APO-LATANOPROST because of possible contamination of the old one or may advise you to stop your treatment with APO-LATANOPROST.

If you become pregnant while using APO-LATANOPROST, tell your doctor immediately.

If you are about to be started on any new medicine tell your doctor and pharmacist that you are using APO-LATANOPROST.

Tell all doctors and pharmacists who are treating you that you are using APO-LATANOPROST.

Things you must not do

Do not give APO-LATANOPROST to anyone else, even if they have the same condition as you.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not stop using APO-LATANOPROST without first talking to your doctor. If you stop using your eye drops, your eye pressures may rise again and damage to your eye may occur.

Things to be careful of

Be careful driving or operating machinery until you know how APO-LATANOPROST affects you. APO-LATANOPROST generally does not cause any problems with your ability to drive a car or operate machinery. However, it may cause blurred vision in some people. Make sure you know how you react to APO-LATANOPROST or that your vision is clear before driving a car or operating machinery.

Side effects

Check with your doctor as soon as possible if you have any problems while using APO-LATANOPROST, even if you do not think the problems relate to the medicine or are not listed in this leaflet. Like other medicines, APO-LATANOPROST can cause some side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • a slow change in eye colour over a period of time.
    The iris may become browner in colour and appear darker. This change may be permanent and more noticeable if you are only being treated in one eye.
  • blurred vision, double vision or other visual problems
  • irritation or feeling of having something in the eye.
    This may be worse during the first two or three days of using APO-LATANOPROST.
  • eye pain
  • redness, burning or watering of the eye(s)
  • discharge, itching of the eye(s), crusty eyelashes
  • darkening, thickening, lengthening or an increase in the number of eye lashes and the fine hair on the eyelids
  • misdirected eyelashes sometimes causing eye irritation
  • darkening of the skin of the eyelids
  • crusting, redness, thickening, itching or burning of the eyelids
  • sensitivity to light
  • skin rash
  • headache
  • muscle/joint pain
  • painful, urgent or frequent urination.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • chest pain
  • you notice strong, rapid or irregular heartbeats
  • dizziness
  • white deposits or plaque in the cornea causing the transparent front part of your eye to look white or cloudy
  • symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Storage and Disposal

Storage

Before opening APO-LATANOPROST, keep the bottle in its box in a refrigerator (2°C - 8°C) protected from light.

After opening APO-LATANOPROST, keep the bottle in its box in a cool place where the temperature stays below 25°C. You do not need to keep it refrigerated. Keep the box properly closed and protected from light.

Do not store this medicine or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Put the top back on the bottle right away after use to avoid contaminating the eye drops.

Disposal

Write the date on the bottle when you open the eye drops and throw out any remaining solution after four weeks.

Open a new bottle every 4 weeks. Eye drops contain a preservative which helps prevent germs growing in the solution for the first four weeks after opening the bottle. After this time there is a greater risk that the drops may become contaminated and cause an eye infection.

If your doctor tells you to stop using the eye drops or they have passed their expiry date, ask your pharmacist what to do with any remaining solution.

Product description

What it looks like

APO-LATANOPROST eye drops come in a plastic bottle with a dropper and screw cap inside a protective overcap. Remove this overcap before use.

When you first receive your APO-LATANOPROST bottle, it will appear half full. This corresponds to 2.5 mL of eye drop solution, giving a minimum of 80 drops. This volume is enough to last 4 weeks if used in both eyes. AUST R 291496.

Ingredients

The active ingredient in APO-LATANOPROST eye drops is latanoprost. Each 1 mL of APO-LATANOPROST contains 50 micrograms of latanoprost. Each drop contains about 1.5 micrograms of latanoprost.

This medicine also contains the following:

  • sodium chloride
  • sodium phosphate monobasic monohydrate
  • sodium phosphate dibasic anhydrous
  • water for injections
  • benzalkonium chloride (as a preservative).

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Tel: (02) 8877 8333
Web: www1.apotex.com/au

This leaflet was prepared in September 2018.

Published by MIMS June 2020

BRAND INFORMATION

Brand name

APO-Latanoprost

Active ingredient

Latanoprost

Schedule

S4

 

1 Name of Medicine

Latanoprost.

2 Qualitative and Quantitative Composition

The active ingredient in APO-Latanoprost is latanoprost, a prostaglandin F analogue. APO-Latanoprost contains 50 microgram/mL of latanoprost in an aqueous buffer solution of pH 6.7. Each 5 mL bottle contains 2.5 mL eye drop solution corresponding to a minimum of 80 drops of solution. One drop contains approximately 1.5 microgram latanoprost.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Latanoprost Eye Drops is a sterile, isotonic solution. The solution is a clear and colourless liquid, practically free from visible particles, filled in a polyethylene container.

4 Clinical Particulars

4.1 Therapeutic Indications

Reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

4.2 Dose and Method of Administration

Recommended dosage for adults (including the elderly).

Recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is obtained if APO-Latanoprost is administered in the evening. Systemic absorption can be minimised by pressure on the tear duct immediately after application of the eye drop.
If one dose is missed treatment should continue with the next dose as normal. The dosage of APO-Latanoprost should not exceed once daily since it has been shown that more frequent administration decreases the IOP lowering effect.

Administration.

APO-Latanoprost is effective as a single drug therapy but can also be used in combination with beta-adrenergic antagonists (timolol), adrenergic agonists (dipivefrine hydrochloride), cholinergic agonists (pilocarpine) and carbonic anhydrase inhibitors (acetazolamide) to achieve an additive effect. In case of combined therapy the eye drop products should be administered with an interval of at least five minutes.

Use with contact lenses.

The contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Known hypersensitivity to latanoprost or any of the excipients in APO-Latanoprost.

4.4 Special Warnings and Precautions for Use

Iris pigmentation changes.

Latanoprost 50 microgram/mL eye drops may gradually change eye colour by increasing the amount of brown pigment in the iris. Before treatment is instituted, patients should be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in heterochromia.
This change in eye colour has predominantly been seen in patients with mixed colour irides i.e. blue-brown, grey-brown, green-brown or yellow-brown. The highest incidence was found in patients with green-brown and yellow-brown irides. In patients with homogeneously blue eyes, no change has been observed and in patients with homogenously grey, green or brown eyes, the change has only rarely been seen. The onset of the change is usually within the first eight months of treatment but may occur later in a small number of patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The colour change is due to increased melanin content in the stromal melanocytes of the iris and not to an increase in the number of melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. Patients who develop increased iris pigmentation should be examined regularly and, depending on the clinical situation, treatment may be stopped. No further increase in brown iris pigment has been observed after discontinuation of treatment, but the resultant colour change may be permanent. It has not been associated with any symptom or pathological changes in clinical trials of up to 48 months duration.
Naevi or freckles of the iris have not been affected by treatment.
Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed in long term clinical trials.

Eyelid and eyelash changes.

Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost 50 microgram/mL eye drops.
Latanoprost 50 microgram/mL eye drops may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation and number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Use with caution in the following circumstances.

Macular oedema.

Macular oedema, including cystoid macular oedema, has been reported uncommonly during treatment with latanoprost 50 microgram/mL eye drops. These reports have mainly occurred in patients with aphakia or pseudophakia with anterior chamber lenses and/or torn posterior lens capsule, or in patients with known risk factors for macular oedema. Caution is recommended when using latanoprost 50 microgram/mL eye drops in these patients. Upon discontinuation of latanoprost 50 microgram/mL eye drops treatment, visual acuity has improved, in some cases with concurrent treatment with topical steroidal and non-steroidal anti-inflammatory drugs.

Glaucoma.

There is no experience with latanoprost 50 microgram/mL eye drops in inflammatory and neovascular glaucoma, inflammatory ocular conditions or congenital glaucoma. There is limited experience with latanoprost 50 microgram/mL eye drops in chronic angle closure glaucoma (one 12 week study), open angle glaucoma of pseudophakic patients (4 out of 519 patients enrolled in the long term safety study were pseudophakic patients) and in pigmentary glaucoma (one 12 month study). Latanoprost 50 microgram/mL eye drops has no or little effect on the pupil, but there is no experience in acute attacks of closed angle glaucoma. Latanoprost 50 microgram/mL eye drops should be used with caution in these conditions until more experience is obtained.

Use with contact lenses.

Latanoprost 50 microgram/mL eye drops contains benzalkonium chloride which may be absorbed by contact lenses. The contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.

Asthma.

There is no experience in patients with severe or brittle asthma. Such patients should therefore be treated with caution until there is sufficient experience (see Section 4.8 Adverse Effects (Undesirable Effects)).

Herpetic keratitis.

Use with caution in patients with a history of herpetic keratitis, it should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Animal toxicity.

The ocular as well as systemic toxicity of latanoprost has been investigated in several animal species. Intravenous acute toxicity studies (2 mg/kg) and oral acute toxicity studies (50 mg/kg) in rats and mice resulted in no mortality. Latanoprost, 2-6 microgram/kg body weight, administered intravenously to unanaesthetised monkeys have been shown to increase the respiration rate probably reflecting bronchoconstriction of short duration.
In animal studies latanoprost has not been found to have sensitising properties.
In the eye no significant toxic effects have been detected with doses of up to 100 microgram/eye/day in rabbits or monkeys (clinical dose is approximately 1.5 microgram/eye/day). In monkeys, however, latanoprost has been shown to induce increased pigmentation of the iris. The mechanism of increased pigmentation seems to be stimulation of melanin production in melanocytes of the iris with no proliferative changes observed. The change in iris colour may be permanent.
In chronic ocular toxicity studies, administration of latanoprost at 6 microgram/eye/day has also been shown to induce increased palpebral fissure. This effect is reversible and occurs at doses above the clinical dose level. The effect has not been seen in humans.

Use in the elderly.

No data available.

Paediatric use.

Latanoprost 50 microgram/mL eye drops is not recommended for use in children. Use in children has not been studied.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions with other medications other than those described, see Section 5.1 Pharmacodynamic Properties, Clinical trials have not been investigated.
There have been reports of paradoxical elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Latanoprost had no effect on male or female fertility studies in rats when administered intravenously with 250 microgram/kg.
(Category B3)
The safety of latanoprost 50 microgram/mL eye drops for use in human pregnancy has not been established. Reproductive studies have been performed in rats and rabbits and no malformations or structural variations were observed in the fetuses at any doses of latanoprost. In rabbits given latanoprost IV at 5 microgram/kg/day, a slight increase of litter resorption occurred and at doses of 50 or 300 microgram/kg/day, total litter resorption (100%) in all animals was recorded. A dose of 1 microgram/kg/day was well tolerated in rabbits.
In pregnant rats dosed with tritium labelled latanoprost intravenously, the radioactivity was detected in all maternal tissues, placenta and fetus.
Latanoprost 50 microgram/mL eye drops should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There are limited experimental animal and no human data available on the pharmacokinetics of latanoprost 50 microgram/mL eye drops in lactation. The active substance in latanoprost 50 microgram/mL eye drops and its metabolites may pass into breast milk and latanoprost 50 microgram/mL eye drops should therefore be used with caution in nursing women.
The benefits of treatment with latanoprost 50 microgram/mL eye drops should clearly outweigh the possible risks for use in nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

In common with other eye preparations, installation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Adverse events occurring at a frequency of > 1% in 6 month comparative trials are presented in Table 1.

Adverse reactions (see Section 4.4 Special Warnings and Precautions for Use).

Most of the adverse events reported for latanoprost relate to the ocular system. The adverse reactions are summarised below according to frequency and system organ class.

Very common (> 10% patients).

Eye disorders.

Iris hyperpigmentation; eye irritation (burning, grittiness, itching, stinging and foreign body sensation); eyelash and vellus hair changes (increased length, thickness, pigmentation and number of eyelashes).

Common (1-10% patients).

Eye disorders.

Mild to moderate ocular hyperaemia; punctate keratitis (mostly without symptoms); blepharitis; eye pain; conjunctivitis; vision blurred; eyelid oedema, localised skin reaction on the eyelids.

Musculoskeletal and connective tissue disorders.

Myalgia, arthralgia.

Nervous system disorders.

Dizziness; headache.

Skin and subcutaneous tissue disorders.

Rash.

Uncommon (> 1% patients).

Eye disorders.

Iritis, uveitis; keratitis; macular oedema including cystoid macular oedema; photophobia.

General disorders and administration site conditions.

Chest pain.

Respiratory, thoracic and mediastinal disorders.

Asthma; dyspnoea.

Rare (< 0.1% patients).

Eye disorders.

Corneal oedema; corneal erosion; periorbital oedema; darkening of the palpebral skin of the eyelids; periorbital and lid changes resulting in deepening of the eyelid sulcus; trichiasis.

Respiratory, thoracic and mediastinal disorders.

Asthma aggravation; acute asthma attacks.

Infections and infestations.

Herpetic keratitis.

Additional information for selected adverse reactions.

Iris pigmentation changes.

Latanoprost 50 microgram/mL eye drops may cause an increase in brown pigmentation of the iris, predominantly in patients with mixed coloured irides, (i.e. blue-brown, grey-brown, green-brown, yellow-brown). This is due to increased melanin content in the stromal melanocytes of the iris (see Section 4.4 Special Warnings and Precautions for Use).

Macular oedema.

Macular oedema has been reported uncommonly during latanoprost 50 microgram/mL eye drops treatment. These reports have mainly occurred in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lens, or in patients with known risk factors for cystoid macular oedema (such as diabetic retinopathy and retinal vein occlusion). An association between the use of latanoprost 50 microgram/mL eye drops and unexplained macular oedema cannot be excluded (see Section 4.4 Special Warnings and Precautions for Use).

Iritis/uveitis.

Cases of iritis/uveitis have been uncommonly reported. The majority of patients in these cases had concomitant predisposing factors for developing iritis/uveitis.

Asthma/dyspnoea.

Cases of asthma and dyspnoea have been uncommonly reported. Rare cases of asthma aggravation and acute asthma attacks have also been reported. There is limited experience from patients with asthma, but latanoprost has not been found to affect the pulmonary function when studied in a small number of steroid and non-steroid treated patients suffering from moderate asthma. There is no experience in patients with severe or brittle asthma and such patients should therefore be treated with caution until there is sufficient experience.

Post-marketing experience.

Eye disorders.

Pseudopemphigoid of ocular conjunctiva, iris cyst.

Cardiac disorders.

Angina, palpitations, angina unstable.

Skin and subcutaneous tissue disorders.

Pruritus.

Adverse reactions for eyedrops containing phosphate buffers.

Cases of corneal calcification have been reported very rarely in association with the use of phosphate-containing eye drops in some patients with significantly damaged corneas.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Apart from ocular irritation and conjunctival or episceral hyperaemia, the ocular effects of latanoprost administered at high doses are not known.

Treatment.

If overdosage with APO-Latanoprost occurs, treatment should be symptomatic and supportive. If APO-Latanoprost is accidentally ingested the following information may be useful: One bottle contains 125 microgram latanoprost. More than 90% is metabolised during the first pass through the liver. Intravenous infusion of 3 microgram/kg in healthy volunteers induced no symptoms but a dose of 5.5-10 microgram/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. In patients with bronchial asthma bronchoconstriction was not induced by latanoprost when applied topically on the eyes in a dose of seven times the clinical dose of APO-Latanoprost.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Latanoprost, a selective prostaglandin F analogue, is a selective prostanoid FP receptor agonist which reduces the intraocular pressure (IOP) by increasing the outflow of aqueous humour. Reduction of the IOP in man starts about three to four hours after administration and maximum effect is reached after 8 to 12 hours. Pressure reduction is maintained for at least 24 hours. Studies in animals and man indicate that the main mechanism of action is increased uveoscleral outflow, although some increase in outflow facility (decrease in outflow resistance) has been reported in man.
Clinical trials have shown that latanoprost has no significant effect on the production of aqueous humour. Latanoprost has not been found to have any effect on the blood aqueous barrier.
Latanoprost has no or negligible effects on the intraocular blood circulation when used at the human clinical dose, as studied in monkeys. However, mild to moderate conjunctival or episcleral hyperaemia may occur during topical treatment.
Chronic treatment with latanoprost in monkey eyes which had undergone extracapsular lens extraction did not affect the retinal blood vessels as determined by fluorescein angiography.
Latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes during short term treatment.
Latanoprost in clinical doses has not been found to have any significant pharmacological effects on the cardiovascular or respiratory systems.

Clinical trials.

Efficacy.

In three pivotal, randomised, double blind, parallel group trials latanoprost 50 microgram/mL once a day was compared with timolol 5 mg/mL twice a day. Across the three trials, 460 patients received latanoprost and 369 received timolol. At 6 months latanoprost reduced IOP by 27-34% from the untreated baseline of 24.4-25.2 mmHg and timolol reduced IOP by 20-33% from a baseline of 24.1-25.4 mmHg. In one of these three studies, the difference between the reduction in IOP by latanoprost versus timolol was statistically significant (p < 0.001). A meta-analysis of the three trials demonstrated that of the intention-to-treat population, 61% of latanoprost treated patients, compared with 40% of timolol treated patients, reached a 30% reduction in diurnal IOP after 6 months. No tolerance to the effect of latanoprost was seen after 12 months in these trials.
The pivotal studies have demonstrated that latanoprost 50 microgram/mL eye drops is effective as monotherapy. In addition, latanoprost 50 microgram/mL eye drops is effective as adjunctive therapy in reduction of IOP. Short term (1 or 2 week) studies suggest the effect of latanoprost is additive in combination with adrenergic agonists (dipivefrine hydrochloride), carbonic anhydrase inhibitors (acetazolamide) and at least partly additive with cholinergic agonists (pilocarpine). Although intended primarily as a safety study, IOP reduction was effectively maintained over 48 months in a clinical trial of 356 patients receiving latanoprost as adjunctive therapy to various medications including β-adrenergic antagonists, adrenergic agonists, cholinergic agonists and carbonic anhydrase inhibitors. Out of 519 patients at study start, only 7 patients were withdrawn from the study due to uncontrolled IOP.
Clinical trials involving a fixed combination of latanoprost 50 microgram/mL and timolol 5 mg/mL given once daily have also been conducted. The mean diurnal IOP-lowering effect of the combination was greater than that produced by monotherapy with either latanoprost 50 microgram/mL once daily or timolol 5 mg/mL bd.

Safety.

Long term safety of latanoprost has been investigated in an open label, multicentre, safety study. This trial enrolled 519 patients, 356 of whom continued for 48 months. Iris pigmentation changes have been observed in patients of the pivotal clinical trials of latanoprost (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). The long term safety study has shown that this change is not associated with any increased risk of clinically significant ocular or systemic effects, nor is it considered to have any long term consequences.
In those patients experiencing colour change, the time to onset of increased iris pigmentation usually occurred within 8 months of starting treatment. Within 24 months, onset had occurred in almost all of these cases. Onset after 36 months of treatment was very rare. Using iris photography, the increase in iris pigmentation was graded as "weak" in 75 out of 124 patients (60.5%) during the first year of onset. A weak grading was maintained in 42 of these patients (33.9%) over 48 months of treatment. In those patients showing iris pigmentation progression, there was no apparent increase in iris pigmentation during the fourth year of treatment, indicating a plateau in pigmentation had been reached. A separate safety study has also shown that reintroduction of latanoprost to patients with increased iris pigmentation will not necessarily lead to a further increase in iris pigmentation severity.
IOP reduction between patients who developed iris pigmentation, and those who did not, was shown to be comparable over 48 months. Table 2 shows the mean IOP and change from baseline in patients experiencing increased iris pigmentation (IIP) and those not experiencing increased iris pigmentation (NIIP).

5.2 Pharmacokinetic Properties

Latanoprost is an isopropyl ester pro drug which is inactive, but after hydrolysis to the acid of latanoprost, becomes biologically active.
The pro drug is well absorbed through the cornea and all drug that enters the aqueous humour is hydrolysed during the passage through the cornea.
Studies in man indicate that the peak concentration in the aqueous humour is reached about two hours after topical administration. After topical application in monkeys latanoprost is distributed primarily in the anterior segment, the conjunctivae and the eye lids. Only minute quantities of the drug reach the posterior segment.
Following an ocular dose of latanoprost, 45% of latanoprost acid is absorbed systemically, with 90% being bound to plasma proteins.
There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. Following intravenous administration in man, the half life in plasma is 17 minutes.
The main metabolites, the 1,2-dinor and 1, 2, 3, 4-tetranor metabolites, exert no or only weak biological activity in animal studies and are excreted primarily in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

Latanoprost was not mutagenic in gene mutation assays in bacteria and mouse lymphoma L5178Y cells and was negative in studies of unscheduled DNA synthesis. Chromosome aberrations were observed with human lymphocytes in vitro but latanoprost did not induce micronucleus formation in vivo.

Carcinogenicity.

Latanoprost was not carcinogenic in either rats or mice when administered by oral gavage at doses up to 170 microgram/kg/day for 24 and 20 months respectively.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients in APO-Latanoprost are sodium chloride, monobasic sodium phosphate monohydrate, dibasic anhydrous sodium phosphate, water for injections and benzalkonium chloride (200 microgram/mL) as a preservative agent.

6.2 Incompatibilities

In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with latanoprost 50 microgram/mL eye drops. If such drugs are used the eye drops should be administered with an interval of at least five minutes.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store unopened bottle at 2°C to 8°C. Refrigerate. Do not freeze. Protect from light.
Store opened bottle below 25°C. Store in the outer cardboard carton.
To be used within 4 weeks after opening.

6.5 Nature and Contents of Container

APO-Latanoprost is supplied in packs* of 1 x 2.5 mL, 3 x 2.5 mL and 6 x 2.5 mL. LDPE bottles.
*Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The structural formula is as follows:
The chemical name of latanoprost is isopropyl-(Z)-7[(1R,2R,3R,5S) 3,5-dihydroxy-2-[(3R)-3- hydroxy-5-phenyl-1-pentyl] cyclopentyl]-5-heptenoate, according to IUPAC. Its molecular formula is C26H40O5 and its molecular weight is 432.58.
Latanoprost is a viscous oil which is practically insoluble in water, freely soluble in ethanol, ethyl acetate, isopropanol, methanol, acetone and octanol, and very soluble in acetonitrile.
Sixty four isomers of latanoprost are possible, however, for APO-Latanoprost it is purified as a single isomer.

CAS number.

The CAS number for latanoprost is 130209-82-4.

7 Medicine Schedule (Poisons Standard)

S4, Prescription Only Medicine.

Summary Table of Changes